Optical coherence tomography (OCT) is a powerful tool for assessing three-dimensional (3D) tissue architectural morphology in vivo and in real-time, with a resolution approaching that of standard histopathology. Optical coherence microscopy (OCM) combines OCT with confocal microscopy in order to achieve high transverse resolution and 3D visualization of cellular features. However, current OCT and OCM imaging technologies have not been able to leverage the advances in molecular-targeted contrast agents because there is no known method to generate molecular contrast using OCT and OCM. Our hypothesis is that 3D, multi-scale OCT and OCM, in combination with molecular-targeted contrast agents, will improve the sensitivity and specificity of early cancer detection. The goal of this program is to develop the technology that will enable molecular contrast for 3D-OCT and OCM imaging, building upon preliminary studies conducted by the candidate. The candidate, Dr. Chao Zhou, completed rigorous training in physics from the University of Pennsylvania and is continuing his postdoctoral research at the Massachusetts Institute of Technology (MIT). He has a solid background in biomedical optical imaging techniques and in pre-clinical research. The K99/R00 award would provide additional research and clinical training under co-mentorship from: Dr. James G. Fujimoto, an international authority on OCT technologies at MIT;Dr. John V. Frangioni, a distinguished leader in molecular imaging at Beth Israel Deaconess Medical Center (BIDMC) and the Harvard Medical School (HMS);and Dr. James L. Connolly, a world renowned breast pathologist at BIDMC and HMS. The unique environments provided by MIT and HMS will encourage successful research, which will vertically integrate technical development in OCT and OCM, and leverage recent advances in molecular-targeted contrast agents and nanotechnology. The successful completion of this program will: 1) transform the OCT field by enabling molecularly sensitive contrast and 3D structural imaging;2) open the way for the highly sensitive and specific detection of cancer markers that can be readily combined with photothermal therapeutic techniques;and 3) serve as a launching point for additional OCT and OCM studies of other pathologies associated with abnormal protein expression levels, such as neurodegenerative and cardiovascular diseases. These advances will enable both the structure and pathological states of tissue to be imaged in 3D, in vivo, in real time, and with micron-level spatial resolutions at multiple scales. Dr. Zhou will also obtain valuable training and research experience so that he will be qualified to lead an independent research program and to compete for independent research funding. PUBLIC HEALTH RELEVANCE: This program will develop and validate an integrated, ultrahigh-speed optical coherence tomography (OCT) and optical coherence microscopy (OCM) system that enables molecularly targeted imaging in 3D, in vivo, in real-time, and with micron-scale spatial resolution. We hypothesize that the combination of 3D, multiple-scale, and molecular-targeted OCT and OCM imaging will greatly enhance the sensitivity and specificity for early cancer detection. This K99/R00 application will also serve as a training vehicle for the candidate, as he transitions to independent investigation.